| Structural highlights
Function
POLG_WNV9 Plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle (PubMed:22925334). During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins. Can migrate to the cell nucleus where it modulates host functions. Overcomes the anti-viral effects of host EXOC1 by sequestering and degrading the latter through the proteasome degradation pathway.[UniProtKB:P17763][1] Inhibits RNA silencing by interfering with host Dicer.[UniProtKB:P03314] Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH6.0. After virion release in extracellular space, gets dissociated from E dimers.[UniProtKB:P17763] Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is the only viral peptide matured by host furin in the trans-Golgi network probably to avoid catastrophic activation of the viral fusion activity in acidic Golgi compartment prior to virion release. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.[UniProtKB:P17763] May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.[UniProtKB:P17763] Binds to host cell surface receptor and mediates fusion between viral and cellular membranes. Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM. They play a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimer between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.[UniProtKB:P17763] Involved in immune evasion, pathogenesis and viral replication. Once cleaved off the polyprotein, is targeted to three destinations: the viral replication cycle, the plasma membrane and the extracellular compartment. Essential for viral replication. Required for formation of the replication complex and recruitment of other non-structural proteins to the ER-derived membrane structures. Excreted as a hexameric lipoparticle that plays a role against host immune response. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).[2] [3] [4] [5] [6] Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host alpha/beta interferon antiviral response.[UniProtKB:P14335] Required cofactor for the serine protease function of NS3. May have membrane-destabilizing activity and form viroporins (By similarity).[UniProtKB:P17763][PROSITE-ProRule:PRU00859] Displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity). NS3 supports the separation of RNA daughter and template strands during viral replication. The helicase part is involved in the inhibition of phosphorylation of host STAT1, and thereby inhibition of host type-I IFN signaling (PubMed:29099073). In addition, NS3 assists the initiation of replication by unwinding the RNA secondary structure in the 3' non-translated region (NTR). Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment (By similarity).[UniProtKB:P14335][PROSITE-ProRule:PRU00860][7] Facilitates host membrane remodelling necessary for viral replication by interacting with host RTN3. Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding.[8] [9] Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763] Induces the formation of ER-derived membrane vesicles where the viral replication takes place (PubMed:24465392). Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway (PubMed:15956546). Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment (PubMed:15956546).[10] [11] Replicates the viral (+) and (-) genome, and performs the capping of genomes in the cytoplasm (PubMed:19850911). NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions (PubMed:19850911, PubMed:20685660). Besides its role in RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway (PubMed:20106931). Inhibits host JAK1 and TYK2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (PubMed:15650160).[12] [13] [14] [15]
Publication Abstract from PubMed
The Flavivirus nonstructural protein 1 (NS1) is a conserved, membrane-associated and secreted glycoprotein with replication and immune evasion functions. Secreted NS1 is a hexameric, barrel-shaped lipoprotein that can bind back to the plasma membrane of cells. Antibodies targeting cell surface-associated NS1 can be protective in vivo in a manner dependent on Fc effector functions. We describe here the crystal structure of a C-terminal fragment (residues 172-352) of West Nile (WNV) and Dengue virus NS1 proteins at 1.85 and 2.7 A resolution, respectively. NS1172-352 assembles as a unique rod-shaped dimer composed of a 16-stranded beta-platform flanked on one face by protruding connecting loops. We also determined the 3.0 A resolution structure of WNV NS1172-352 with the protective 22NS1 antibody Fab, which engages the loop-face of the rod. The head-to-head NS1172-352 dimer we observe in crystal lattices is supported by multiangle light and small-angle X-ray scattering studies. We used the available cryo-electron microscopy reconstruction to develop a pseudoatomic model of the NS1 hexamer. The model was constructed with the NS1172-352 dimeric rod aligned with the long axis of the barrel, and with the loop-face oriented away from the core. Difference densities suggest that the N-terminal region of NS1 forms globular lobes that mediate lateral contacts between dimers in the hexamer. Our model also suggests that the N-terminal lobe forms the surface of the central cavity where lipid binding may occur.
Structural basis of Flavivirus NS1 assembly and antibody recognition.,Edeling MA, Diamond MS, Fremont DH Proc Natl Acad Sci U S A. 2014 Mar 4. PMID:24594604[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xu Z, Hobman TC. The helicase activity of DDX56 is required for its role in assembly of infectious West Nile virus particles. Virology. 2012 Nov 10;433(1):226-35. doi: 10.1016/j.virol.2012.08.011. Epub 2012 , Aug 25. PMID:22925334 doi:http://dx.doi.org/10.1016/j.virol.2012.08.011
- ↑ Chung KM, Liszewski MK, Nybakken G, Davis AE, Townsend RR, Fremont DH, Atkinson JP, Diamond MS. West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19111-6. doi: , 10.1073/pnas.0605668103. Epub 2006 Nov 28. PMID:17132743 doi:http://dx.doi.org/10.1073/pnas.0605668103
- ↑ Youn S, Ambrose RL, Mackenzie JM, Diamond MS. Non-structural protein-1 is required for West Nile virus replication complex formation and viral RNA synthesis. Virol J. 2013 Nov 18;10:339. doi: 10.1186/1743-422X-10-339. PMID:24245822 doi:http://dx.doi.org/10.1186/1743-422X-10-339
- ↑ Kaufusi PH, Kelley JF, Yanagihara R, Nerurkar VR. Induction of endoplasmic reticulum-derived replication-competent membrane structures by West Nile virus non-structural protein 4B. PLoS One. 2014 Jan 20;9(1):e84040. doi: 10.1371/journal.pone.0084040. eCollection , 2014. PMID:24465392 doi:http://dx.doi.org/10.1371/journal.pone.0084040
- ↑ Morrison CR, Scholle F. Abrogation of TLR3 inhibition by discrete amino acid changes in the C-terminal half of the West Nile virus NS1 protein. Virology. 2014 May;456-457:96-107. doi: 10.1016/j.virol.2014.03.017. Epub 2014 , Apr 3. PMID:24889229 doi:http://dx.doi.org/10.1016/j.virol.2014.03.017
- ↑ Crook KR, Miller-Kittrell M, Morrison CR, Scholle F. Modulation of innate immune signaling by the secreted form of the West Nile virus NS1 glycoprotein. Virology. 2014 Jun;458-459:172-82. doi: 10.1016/j.virol.2014.04.036. Epub 2014 , May 14. PMID:24928049 doi:http://dx.doi.org/10.1016/j.virol.2014.04.036
- ↑ Setoh YX, Periasamy P, Peng NYG, Amarilla AA, Slonchak A, Khromykh AA. Helicase Domain of West Nile Virus NS3 Protein Plays a Role in Inhibition of Type I Interferon Signalling. Viruses. 2017 Nov 2;9(11):326. doi: 10.3390/v9110326. PMID:29099073 doi:http://dx.doi.org/10.3390/v9110326
- ↑ Shiryaev SA, Chernov AV, Aleshin AE, Shiryaeva TN, Strongin AY. NS4A regulates the ATPase activity of the NS3 helicase: a novel cofactor role of the non-structural protein NS4A from West Nile virus. J Gen Virol. 2009 Sep;90(Pt 9):2081-5. doi: 10.1099/vir.0.012864-0. Epub 2009 May , 27. PMID:19474250 doi:http://dx.doi.org/10.1099/vir.0.012864-0
- ↑ Aktepe TE, Liebscher S, Prier JE, Simmons CP, Mackenzie JM. The Host Protein Reticulon 3.1A Is Utilized by Flaviviruses to Facilitate Membrane Remodelling. Cell Rep. 2017 Nov 7;21(6):1639-1654. doi: 10.1016/j.celrep.2017.10.055. PMID:29117567 doi:http://dx.doi.org/10.1016/j.celrep.2017.10.055
- ↑ Munoz-Jordan JL, Laurent-Rolle M, Ashour J, Martinez-Sobrido L, Ashok M, Lipkin WI, Garcia-Sastre A. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol. 2005 Jul;79(13):8004-13. PMID:15956546 doi:10.1128/JVI.79.13.8004-8013.2005
- ↑ Kaufusi PH, Kelley JF, Yanagihara R, Nerurkar VR. Induction of endoplasmic reticulum-derived replication-competent membrane structures by West Nile virus non-structural protein 4B. PLoS One. 2014 Jan 20;9(1):e84040. doi: 10.1371/journal.pone.0084040. eCollection , 2014. PMID:24465392 doi:http://dx.doi.org/10.1371/journal.pone.0084040
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Issur M, Geiss BJ, Bougie I, Picard-Jean F, Despins S, Mayette J, Hobdey SE, Bisaillon M. The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure. RNA. 2009 Dec;15(12):2340-50. doi: 10.1261/rna.1609709. Epub 2009 Oct 22. PMID:19850911 doi:10.1261/rna.1609709
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Dong H, Liu L, Zou G, Zhao Y, Li Z, Lim SP, Shi PY, Li H. Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. J Biol Chem. 2010 Oct 15;285(42):32586-95. Epub 2010 Aug 4. PMID:20685660 doi:10.1074/jbc.M110.129197
- ↑ Edeling MA, Diamond MS, Fremont DH. Structural basis of Flavivirus NS1 assembly and antibody recognition. Proc Natl Acad Sci U S A. 2014 Mar 4. PMID:24594604 doi:http://dx.doi.org/10.1073/pnas.1322036111
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